Abstract
Increasing evidence suggests thrombospondin-1 (TSP-1), a potent proatherogenic matricellular protein, as a putative link between hyperglycemia and atherosclerotic complications in diabetes. We previously reported that the micronutrient chromium picolinate (CrP), with long-standing cardiovascular benefits, inhibits TSP-1 expression in glucose-stimulated human aortic smooth muscle cells in vitro. Here, we investigated the atheroprotective action of orally administered CrP in type 1 diabetic apolipoprotein E-deficient (ApoE−/−) mice and elucidated the role of TSP-1 in this process. CrP decreased lipid burden and neointimal thickness in aortic root lesions of hyperglycemic ApoE−/− mice; also, smooth muscle cell (SMC), macrophage and leukocyte abundance was prevented coupled with reduced cell proliferation. Attenuated lesion progression was accompanied with inhibition of hyperglycemia-induced TSP-1 expression and reduced protein O-glycosylation following CrP treatment; also, PCNA and vimentin (SMC synthetic marker) expression were reduced while SM-MHC (SMC contractile marker) levels were increased. To confirm a direct role of TSP-1 in diabetic atherosclerosis, hyperglycemic TSP-1−/−/ApoE−/− double knockout mice were compared with age-matched hyperglycemic ApoE−/− littermates. Lack of TSP-1 prevented lesion formation in hyperglycemic ApoE−/− mice, mimicking the atheroprotective phenotype of CrP-treated mice. These results suggest that therapeutic TSP-1 inhibition may have important atheroprotective potential in diabetic vascular disease.
Highlights
Tissue-specific effects of TSP-1; both in vivo and in vitro studies have revealed that TSP-1 stimulates VSMC proliferation[12] while inducing endothelial cell (EC) apoptosis[13]
A slight reduction (~15%) in glucose levels was noted at 12 weeks of age following chromium picolinate (CrP) administration, this effect was abolished at later time points and the animals continued to remain hyperglycemic attaining non-fasted blood glucose levels ≥250 mg/dl
The present study provides the first demonstration for an atheroprotective effect of the nutraceutical CrP in a mouse model of diabetic atherosclerosis
Summary
Tissue-specific effects of TSP-1; both in vivo and in vitro studies have revealed that TSP-1 stimulates VSMC proliferation[12] while inducing endothelial cell (EC) apoptosis[13]. The TSP protein family has been previously linked to atherosclerotic vascular disease based on GENEQUEST studies demonstrating an association between specific single nucleotide polymorphisms in the TSP genes with coronary artery disease and myocardial infarction[14]. We have further shown that hyperglycemia in vitro increases TSP-1 expression via a transcriptional mechanism in primary human aortic smooth muscle cell (HASMC) cultures[17,18]. Together, these findings implicate TSP-1 as a putative link between hyperglycemia and accelerated atherosclerotic complications in diabetes. We have shown that genetic deletion of TSP-1 protects ApoE−/− mice against hyperglycemia-induced atherosclerosis, mimicking the protective phenotype of CrP-treated diabetic atherosclerotic mice
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